Method of preparing steroidal 6-chloro-4, 6-dienes



United States 3,294,823 METHUD @F PREFARENG SEERSEDAL 6- CHLGR-4,6-DHENES Yvon L. Lefebvre, Pierrefontls, Quebec, Canada, assignor to American Home Products Qorporation, New York,

N.Y., a corporation of Delaware No Drawing. Filed Nov. 18, 1964, Ser. No. 415,292

5 Claims. (Cl. 250-3973) This application is a continuation-in-part of my copending application, Serial No. 299,158, filed August 1, 1963.

The present invention relates to steroidal 6-chloro-4,6- dienes or" the pregnane, androstane, and cholestane series, which are characterized by possessing the following structure in rings A and B in which Y represents an acyloxy, an hydroxyl, or a keto group, and to methods for their preparation. More specifically, the present invention relates to 6-chloropregna- 4,6-dien-20-ones, and to methods for the preparation of compounds of the general Formulae II and III:

in which R represents hydrogen, acyloxy, or a straight chain lower alkyl group containing from 1-4 carbon atoms, R represents hydrogen or an acyl group, and X represents hydrogen or fluorine.

The new compounds produced in accordance with my invention are useful compounds, in that they are useful in steroid research generally and as intermediates in the preparation of other steroid compounds which are characterized by biological activities. For example, the compounds of this invention in the pregnane series are useful as progestational agents of unusually high potency, and long duration of action, active both by injection and by oral administration. The compounds of this invention in the pregnane series are further distinguished by being useful for maintaining pregnancy. Said compounds have also been found to be substantially free from objectionable side-eifects such as masculinization and suppression of adrenal function, and other compounds of this invention in the pregnane series have been found to possess valuable anti-androgenic activity. Of the other compounds of this invention, 6-chloro-3/3,17,8-diace-toxy-androstal,6- diene has valuable androgenic, anabolic, and gonadotrophin-suppressing properties, and 6-chloro-3/3-hydroxycholesta-4,6-diene is useful as a cholesterol-lowering agent.

The compounds of this invention may be administered in dosage forms such as tablets, capsules, or the like, such dosage forms to contain from 1 to 50 mg. of the active compound per dosage form, the active agent being present in such dosage forms together with excipients such as,

atent O Patented Dec. 27, 1966 lactose, starch, magnesium stearate, and the like, as well as such other substances as are commonly used in the formulation of dosage forms for oral administration. For the purposes of administering the compounds of this invention by injection they may be suspended in a fine state of division in a pharmaceutically acceptable aqueous vehicle, or they may be administered in solution in a pharmaceutically acceptable solvent.

The compounds of this invention corresponding to Formula II in which R, R, and X are as defined above, are also useful as intermediates in the preparation of the compounds of Formula III, in which R and X are as defined above.

The starting materials for the preparation of the compounds of this invention are 3fiacyloxy-A -6-ketosteroids of the pregnane, androstane, and cholestane series possessing the following structure in rings A and B More specifically those starting materials are new 4-pregnene-6,20-diones which maybe represented by the general Formula V C HzX in which R represents hydrogen, a straight chain lower alkyl group containing from 1-4 carbon atoms, or an acyloxy group, X represents hydrogen or fluorine, and R represents an acyl group.

Those compounds in which R represents the acetyl group may be prepared as described in the co-pending U.S. patent application Serial No. 285,210, filed June 4, 1963, in the names of Y. Lefebvre and P. F. Morand and now abandoned. Hydrolysis with bicarbonate yields the corresponding 3fl-hydroxy derivatives, which are esterified with the appropriate acid halides or anhydrides in the presence of pyridine to yield the corresponding 3,8-acyloxypregn-4-ene-6,20-diones.

The Not-acylated 3B-acetoXypregn-4-ene-6,20-diones are prepared from the corresponding l7a-acyloxy pregnenolone acetate by the methods described in the copending U.S. patent application Serial No. 285,210. In this manner there are obtained 3B-acetoxy-17a-propionyloXypregn-4-ene-6,2O dione, Zfi-acetoxy-I7a-butyryloxypregn-4-ene-6,20-dione, 3,8-acetoXy-17u-valeryloxypregn- 4-ene-6,20-dione, and Bfl-acetoxy-l7u-hexanoyloxypregn- 4-ene-6,20-dione.

The latter 17a-acylated 3B-acetoxypregn-4-ene-6,20- diones are selectively hydrolyzed with bicarbonate as above, and the corresponding 3,8-hydroxy derivatives are acylated with the appropriate acid halide or anhydride to yield the corresponding 3/3, 17a-diacyloxypregn-4-ene- 6,20-diones.

With regard to the process aspects of this invention which are novel, my invention is concerned with the treatment of a steroid compound having a double bond between carbon atoms 4 and 5 and a keto (x0) group in the 6-position, whereby an additional double bond is introduced between carbon atoms 6 and 7 and the oxygen in position 6 is replaced by chlorine. As will be explained more fully hereafter, in carrying out this process utilize phosphorus pentachloride as the reagent for treating sm'd steroid.

I have now found that treatment of a 3B-acyloxy-A -6- ketosteroid of Formula IV, or of a 4-pregnene-6,20-dione of a structure corresponding to Formula V with phosphorus pentachloride in an inert solvent yields a compound of the structure represented by Formula I in which Y represents an acyloxy group, or, respectively, of Formula II in which R represents an acyl group and R and X have the significance defined above. The inert solvent must not contain groupings which will react with phosphorus pentachloride and it must not be basic nor a Lewis base. Preferred solvents are aromatic hydro- :arbons, with a boiling point below 150 C., for example, benzene, toluene, or xylene; lower aliphatic esters, for example, methyl or ethyl acetate; and certain halogenated aliphatic hydrocarbons such as, for example, carbon :etracbloride. The course of this reaction is entirely unexpected in that the ZO-keto group of the starting material is not aifected, contrary to the well-known reaction of phosphorus pentachloride with aliphatic ketones. Temperature of the reaction is not critical, although extreme :emperature will decrease the yield of desired end product. Operable temperatures include temperatures between 20 C and the temperature of the boiling reaction mixture, with a temperature range of between 20 and 30 C. being preferred. Similarly, the molar ratio of phosphorus pentachloride to fi-keto steroid is not critical but affects the speed of reaction? For example, this molar ratio may be varied from 1:1 to :1 with ensuing speeding up of the reaction; with a 1:1 molar ratio of reactants the reaction is essentially complete in from one to two hours; with a 2:1 molar ratio, in approximately one-half hour; and with a 5:1 molar ratio, in approximately five minutes.

I have found, in a preferred embodiment of this invention, that it is advantageous to add a base which is soluble in the reaction mixture such as, for example, pyridine, or a Lewis base which is also soluble in the reaction mixture such as, for example, dioxane, to the reaction mixture a short time after the spontaneous start of the reaction in amounts inferior to those necessary to stop the reaction. In one particular embodiment of my invention addition of one molar equivalent of such a baseor Lewis base has been found to improve yields by a factor of at least three.

After completion of the reaction the desired end product is recovered from the reaction mixture by conventional means. In a preferred reaction procedure an organic base soluble in the solvent employed, such as, for example, pyridine, is added at the end of the reaction in amounts suflicient to stop the reaction. Amounts of two to three moles per mole of PCl have been found sufficient for this purpose. The precipitate thus obtained may be removed by filtration. The filtrate contains the desired steroidal 6-chloro-4,6-diene of Formula I in which Y represents an acyloxy group, or, respectively, the 6-c-hloropregna-4,6-dien-20-one of Formula II in which R represents an acyl grouping, and R and X are as defined above. The latter compound is isolated by evaporation of the solvent and purified by conventional procedures such as, for example, chromatography and or crystallization.

The 3-acylat-es of the steroidal 6-ch-loro-4,6-dienes or 6-ohloropregna-4,6-dien-20-ones obtained above are hydrolyzed in a basic medium to 'yield the corresponding steroidal 6-chloro-4,6-dienes of Formula I in which Y represents an hydroxyl group, or, respectively, the 6- .4 ohloro-3 8-hydroxy-pregna-4,6-dien-20-ones of Formula II in which R represents hydrogen and R and X have the. significance defined above. The latter compounds are oxidized by conventional means such as, for example, the Oppenauer method or by hexavalent chromium ion, to the corresponding steroidal 6-chloro-4,6-dienes of Formula I in which Y represents a ket-o group, or, respectively, the 6-chloro-fi-dehydroprogesterones of Formula III in which R and X have the significance defined above. The latter compounds may again be reduced to the corresponding 3,8-alcohols of Formula I or II in which Y represents an hydroxyl group, or in which R represents hydrogen, respectively, by reaction with a reducing agent, such as, for example, sodium borohydride or lithium tri-(tertiary butoxy) aluminum hydride.

More specifically, 313-21cetoxypregn-4-ene-6,20-dione (V, R'=CH CO, R=X=H) yields 3B-acetoxy-6-chloropregna-4,6-dien20-one (II, R' CH CO, R X H); which may be hydrolyzed to the corresponding alcohol, 6-chloro-3,8-hydroxypregna-4,6-dien-20-one which may in turn 'be oxidized to the corresponding 3- ketone, 6-chloro-6dehydroprogesterone (III, R=X=H). The 3B-acyloxypregn-4-ene-6,20-diones yield the corresponding 3,6-acyloxy-6-chloropregna-4,6-diene-ZO-ones which upon hydrolysis and subsequent oxidation, yield the same compounds as above.

In the same manner, the 3/3-acyloxy-l7a- (lower alkyl)- pregn-4-ene-6,20-diones (V) yield the corresponding 3,8-acyloxy-6-chloro-Not-(lower alkyl)pregna-4-,6-dien-' ZO-ones (II). The latter compounds are hydrolyzed to the corresponding 6-chloro-3fi-hydroxy-17a-(lower alkyd)- pregna-4,6-dien-20-ones (II, R'=H), which are in turn oxidized to the corresponding 6chloro-6-dehydro-17a- (lower alkyl) progesterones (III).

More specifically, 3,8-acetoxy-17ot-methylpregn-4-ene- 6,20-dione (V, R=CII CO, R=CH X=H) yields 3B- acetoxy-6-ch1oro-l7at-methylpregna-4,6-dien-ZO-one The latter compound is hydrolyzed to the corresponding alcohol, 6-chl0ro-3fi-hydroxy-l7a-methylpregna-4,6-dien- 20-one (II, R=CH R'=X=H), which is oxidized to the corresponding 6-chloro-6-dehydro-17m-methylprogesterone (III, R:CH X=H). In a similar manner other corresponding t-1OW61' alkyl compounds, such as the 3/8-acetoxy-6-chloro-l7u-ethylpregna-4,6-dien-20- one, 35 acetoxy-6-ohloro-l7a-n-propyl-pregna-4,6-dien- 20 one, 35 acetoxy 17a-n-butyl-6-chloropregna-4,6- dien-ZO-one, and their corresponding products of hydrolysis and oxidation may be obtained.

In a similar manner, the 3,8-acyloxy-2l-fluoro-17a- (lower alkyl)pregn-4-ene-6,20-diones (V) yield the 3B- acyloxy-6-chloro-2 l-fiuoro-l 7a- (lower alkyl) pregna-4,6- dien-20-ones (II). The latter compounds are hydrolyzed to the corresponding 6-chloro-2l-fluoro-3fl-hydroxy-l7m- (lower alkyl)pregna-4,6-dien-20-ones (II, R'=H), which are in turn oxidized to the corresponding 6-chloro-6- dehydro-Zl-fluoro-l7a(lower alky1)progesterones (III).

More specifically, 3B-acetoxy-21-fluoro-l7a-methylpregn-4-ene-6,20-dione (V, R'=CH CO, R=CH X=F), yields 3B-acetoxy-6-chloro-21-fluoro-17tx methylpregna- 4,6-dien-20-one The latter compound may be hydrolyzed to the corresponding alcohol, 6-chloro-2l-fiuoro 313 hydroxy 17amethylpregna-4,6-dien-20one (II, R'=H, R=CH X=F) which may be oxidized to 6-chloro-6-dehydro-2l-fluorol7ot-methylprogesterone (III, X=F, R=CH The same sequence of reactions may also be carried out with the other corresponding l7a-lower alkyl-Zl-fiuoro compounds such as the 17a-ethyl, 17a-n-propyl and 170:- n-butyl compounds to yield the corresponding 3pacetoxy- 6-chloro-21-fiuoro-17a-(lower alkyl)-pregna-4,6-dien-20- ones, and their corresponding products of hydrolysis and oxidation; in the same manner, the corresponding 3/3- acyloxy-Z1-fluoropregn-4-ene-6,20-diones yield 3B-acyloxy-6-chloro-21-fiuoro-pregna-4,6-dien-20-ones and their products of hydrolysis and oxidation.

In a similar manner, 35, 17a-diacyloxypregn-4-ene-6, 20 diones (V) yield 6 chloro 3,8, 17oz diacyloxypregna 4,6 dien 20 ones (II), which are hydrolyzed to the corresponding 17a-acyloxy-6-chloro-3B-hydroxypregna-4,6-dien-20-ones (II, R'=H), which are in turn oxidized to the corresponding 17a-acyloxy-6-chloro-6-dehydro progesterones (III). The latter compounds are in turn reduced to their precursors (11). Similarly, the corresponding compounds of Formula II in which the 2l-position is substituted by fluorine, and their products or" hydrolysis and oxidation, are prepared.

ore specifically, 3,6,l7a diacetoxypregn 4 ene- 6,20 dione (V, R=CH CO, R=CH COO, X=H) yields 6 chloro 3,8-17u diacetoxy pregna 4,6- dien-ZO -one (II, R=CH CO, R=CH COO, X=H). The latter compound is hydrolyzed to 17a-acetoxy-6- chloro-3;8-hydroxy-pregna-4,6-dien-20-one (II, R=X=H, R CH COO) which is oxidized to 17a-acetoxy-6-chloro-6-dehydroprogesterone (III, R=CH COO, X=II). The latter compound is reduced to its precursor Similarly, 17a-acetoxy-3,B-hexanoyloxypregn-4-ene-6, 20-dione and 17a-acetoxy-3B-[3'-(cyclopentyl)] propionyloxypregn-4-ene-6,20-dione (both prepared from the corresponding 3B,l7a-diacetoxy derivative by hydrolysis and re-esterification with the appropriate acylating agent) yield 17a-acetoxy-6-chlor0-3,B-hexanoyloxypregna-4,6-dien-20-one, and l7a-acetoxy-6-chloro-3fi-[3- (cyclopentyl)] propionyloxypregnal,6-dien-20-one, respectively. Their respective products of hydrolysis and oxidation are obtained as above.

In the same manner the corresponding compounds in which the l7a-hydroxy group is esterified with lower aliphatic acids such as, for example, the 17oc-l1YdfOXY hexanoate, are prepared. Examples of compounds which are obtained in the above manner include 6-Cl'11O1O,3,B,170c diacetoxy-Z1-fiuoropregna-4,6-dien-20-one and its products of hydrolysis and oxidation, 3B-acetoxy-6-chloro2 fluoro-17a-hexanoyloxypregna-4,6-dien-20-one and its products of hydrolysis and oxidation, and 3 8-acetoxy-6- chloro-17e-hexanoyloxypregna-4,6-dien-20-one and its products of hydrolysis and oxidation.

In a similar manner, the 3 3,17/3-diacyloxyandrost-4- ene-6-ones yield the corresponding 6-chloro-3,8,17[3-diacyloxyandrosta-4,6-dienes when treated with phosphorus pentachloride. These latter compounds, upon hydrolysis, yield 6-chloro-3p,l7B-dihydroxyandrosta-4,6-diene, which in turn, upon oxidation, yields 6-chloroandrosta-4,6-diene- 3,17-dione.

In the same manner, the 3 B-acyloxycholest-4-ene6-ones yield the 3l3-acyloxy-6-chlorocholesta-4,6-dienes from which 6-chloro-3fl-hydroxycholesta-4,6-diene is obtained by mild alkaline hydrolysis; oxidation yields 6-chlorocholesta-4,6-dien-3-one.

More specifically, 3B,17fi-diacetoxyandrost-4-ene-6- one, prepared from the known 3,8,17B-diacetoxy-5a-hydroxyandrostan-6-one by treatment with thionyl chloride, yields 6-chloro-3fi,l7B-diacetoxyandrost-4,6-diene when treated with phosphorus pentachloride. In the same manner, the known 3,B-acetoxycholest-4-ene-6-one yields, upon treatment with phosphorus pentachloride, 3;8-acetoxy- 6-chlorocholesta-4,6-diene, from which the corresponding 6? 3,8-hydroxy compound, 6-chloro-3,6-hydroxycholesta-4,6- diene, is obtained by mild alkaline hydrolysis.

The following examples will illustrate my invention:

Example 1 .-3 fi-acetoxy-d -ch lor0pregIza-4 ,6 -d ien-ZO-Onc A mixture of 3fl-acetoxypregnt-ene-6,2O-dione (10.8 g.) phosphorus pentachloride (10.8 g.) and benzene (518 cc.) is stirred at room temperature for one minute. Then dioxane (4.4 cc.) and benzene (52 cc.) are added and the stirring is resumed for thirty minutes at room temperature. At the end of this time pyridine (12 cc.) is added. Pyridine hydrochloride is filtered, well washed with ether, and the filtrate is washed with sodium bicarbonate, water, dried, and evaporated, leaving crude 3fi-acetoxy-6-chloropregna-4,6-dien-20-one. Purification by chromatography on florisil gives the pure chloroderivative, which shows in the ultra-violet spectrum maxima of absorption, characteristic of the system, at 238 m 243 m and 251 mu.

In the same manner the 3B-acyloxypregn-4-ene-6-20- diones yield the corresponding 3,8-acyloXy-6-chloropregna- 4,6-diene-20-ones.

Hydrolysis of the above acylated compounds in a manner similar to that described in Example 3 of this application yields the corresponding alcohol, 6-chloro-3B-hydroxypregnal,6-dien-20-one, which is oxidized to 6- chloro-6-dehydroprogesterone.

dien-ZO-one A mixture of 2.375 g. of 3,8-acetoxy-17a-methylpregn- 4-ene-6,20-dione, 2.375 g. of phosphorus pentachloride in cc. of dry benzene, is stirred for 30 minutes at room temperature. The solution is poured in ice-water and the benzene solution is washed with sodium bicarbonate and water, is dried, and evaporated to dryness. Chromatography and crystallization from methanol gives the pure 35 acetoxy 6 chloro 17a methylpregna 4,6 dien- 20-one, M.P. 139l41 C.. [oc] =67.6.

Calculated for C H O Cl: C%, 71.18; H%, 8.21; Cl%. 8.75. Found: (3%, 70.94; H%, 8.28; Cl%, 8.70.

Alternatively, a mixture of 1 g. of 3t3-acetoxy-17amethylpregn-4-ene-6,20-dione, and 1 g. of phosphorus pentachloride in 50 cc. of dry benzene is stirred at room temperature for one minute. A solution of 0.4 cc. of dry dioxane in 5 cc. benzene is then added and the reaction is allowed to proceed for thirty minutes.

The reaction mixture is poured in an ice-cold sodium bicarbonate solution. The organic layer is decanted, washed free of base, dried and evaporated. The residue is a yellow resin, which upon chromatography on fiorisil and crystallization from methanol yields 3/i-acetoxy-6- chloro-17u-methylpregna-4,6-dien-20-one, M.P. 136-141 C.

Similarly,a mixture of 1 g. of 3/3-acetoxy-17u-methylpregn-4-ene-6,20-dione, 1 g. of phosphorus pentachloride and 50 cc. of benzene is stirred for a minute. Then at regular intervals (three minutes) are introduced small portions of a solution of 0.35 cc. of pyridine in 5 cc. of benzene. After thirty minutes the remainder of the pyridine solution is added.

The reaction is worked up as described above to yield 3fi-acetoxy 6 chloro-17a-methy1pregna4,6-dien-20-one, M.P. 136-139 C.

Similarly, a mixture of 200 mg. of 3fiacetoxy-17amethylpregn-4-ene-6,ZO-dione, 200 mg. of phosphorus tpentachloride, and 10 cc. of carbon tetrachloride is stirred at room temperature for 30 minutes, and 0.1 cc. of pyridine is added at the end of the reaction. Working up as described above and crystallization from methanol yields 3 ,8-acetoxy-6-chloro-17 omethy1pregna-4,6-dien-20- one, M.P. 138143 C.

In the same manner, a mixture of 200 mg. of 3B-acetoxy-l7a methylpregn-4-ene6,20-dione, 200 mg. of phosphorus pentachloride and 10cc. ethyl acetate is stirred 7 at room temperature for 30 minutes, and 0.1 cc. of pyridine is added at the end of the reaction. Working up as described above yields 3fi-acetoxy-6-chloro-Not-methylpregna-4,6-dien-20-one identified with an authentic sample by thin-layer chromatography.

In the same manner, the 3fl-acyloxy-l7e-(lower alkyl) pregn-4-ene-6,20-diones (V) yield the corresponding 36- acyloxy-6-chloro-l7u-(lower alkyl).pregna-4,6 dien 20- ones.

Example 3.-6-chl0r0-35-hydroxy-17a-methylpregna- 4,6-dien-20-0ne A solution of 35-acetoxy-6-chloro-17oumethylpregna-4,

6-dien-20-one (5.3 g.), potassium bicarbonate (1.37 g), methanol (215 cc.) and water (21.5 cc.) is refluxed under nitrogen for 30 minutes.

To the still hot solution water is added and the resulting solid is filtered and dried M.P. 187.5l88.5 C. Further crystallization from methylene chloride-hexane does not raise the melting point of 6-chloro-3B-hydroxy- 17u-rnethylpregna-4,6-dien-20-one. The ultra-violet spectrum shows maxima of absorption at 237 m 244 mu (e=22590), 252 m and 287 m 67-4).

In the same manner, the corresponding 3fi-acyloxy-6- chloro-l7u-(lower alkyl)pregn-4,6-dien-20-ones yield the corresponding 6-chloro 3,9 hydroxy-17a-(lower alkyl) pregna-4,6-dien-20-ones.

Example 4 .-6-ch lr0-6-dehydro-1 7 u-methylprogeszerone To a solution of 6-chloro-3fl-hydroxy-17a-methylpre na-4,6-dien-20one (500 mg.) in acetone (60 cc.) at 0 C., is added a solution of 8 N chromic acid (1 cc.). The mixture is immediately poured on ice-water and etherextracted. The ether is Washed free of acid, dried and evaporated, leaving an amorphous residue. Purification by chromatography and crystallization from hexane gives the pure 6-chloro 6 dehydro-17u-methylprogesterone, M.P. 122l24 C. The infra-red spectrum is identical with that of authentic 6-chloro-6-dehydro-Net-methylprogesterone.

In the same manner, the 6chloro-3fi-hydroxy-17a- (lower alkyl)pregna-4,6,-dien-20-ones are oxidized to yield the corresponding 6-chloro-6-dehydro-17u-(lower alkyl progesterones.

Example .3 B-aceton-ti-chloro-ZI -flu0ro-1 7ozmethylpregna-4,6-dien-20-0ne A mixture of 3/3-acetoxy-21-fluoro-17ot-methylpregn-4- ene-6,20-dione (4.15 g), phosphorus pentachloride (4.15 g.) in benzene (200 cc.) is stirred for one minute at room temperature. A solution of dioxane (1.6 cc.) in pyridine (20 cc.) is then added and stirring is continued for thirty minutes. Pyridine (2.8 cc.) is added and the pyridine hydrochloride is filtered. The filtrate is washed with sodium bicarbonate and water, dried and evaporated, leaving a yellow resin. Crystallization from methanol and from methylene chloride-hexane gives pure 313-acetoxy-6-chloro-21-fluoro 17oz methylpregna-4,6-dien-20- one, M.P. 172173 C. xmax. 236 m 243 m (e=25,800), 250 m 290 mp. (6:77).

Calcd for C H O CIF: C%, 68.14; H%, 7.68; Cl%, 8.39; F%, 4.49. Found: C%, 67.90; H%, 7.71; Cl%, 8.17; F%, 4.44.

Hydrolysis of the above compound in a manner similar to that described in Example 3 of this application yields the corresponding alcohol, 6-chloro-2l-fluoro-ByS-hydroxy- 17a-methylpregna-4,6-dien-20-one.

In the same manner, the 3B-acyloxy2l-fluoro-17u- (lower alkyl)pregn-4-ene-6,20-diones yield the corres- .ponding 3l8-acyloxy-6-chloro-2l-fluoro-l7oc-(lower alkyl) pregna-4,6-dien-20-ones, which are hydrolyzed to yield the corresponding 6-chloro-2l-fluoro-3fi-hydroxy-l7a-(lower alkyl)pregna-4,6-dien-20-ones, which are in turn oxidized to the corresponding 6-chloro-6-dehydro-21-fiuoro-17a- (lower alkyl) progesterones.

8 Example 6.-3,3,17a-diacet0xy-6-chloropregna- 4,6-dien-20-0ne A mixture of 3,6,17u-diacetoxypre-gn-4-ene-6,20-dione (3 g.) phosphorus pentachloride (3 g.) and benzene cc.) is stirred at room temperature for one minute. Then dry dioxane (1.2 cc.) dissolved in benzene (15 cc.) is added and the reaction is continued for thirty minutes. At the end of this time pyridine (2.2 cc.) is added. The pyridine hydrochloride thus formed is filtered and washed with ether. The filtrate is washed with cold sodium bicarbonate, water, dried and evaporated. The residue is a resin which, crystallized from methanol, and then meth ylene chloride-hexane, gives pure 3,B,17m-diacetoxy-6- chloropregna-4,6-dien-20-one, M.P. 202.5204 C. (dec.) [a] =-89.5, Amax. 236 m (e=22,200), 231 m 283 m (6:105).

Calculated for C H O Cl: C%, 66.87; H%, 7.41; Cl%, 7.91. Found: C%, 66.79; H%, 7.42; Cl%, 8.07, 8.06.

Example 7.--] 7 a-acetoxy-6 -ck lore-3 s-lrya roxy pregna- 4,6-dien-20-0ne A mixture of 318,17a-diacetoxy-6-chloropregna4,6- dien-ZO-one (50 mg), potassium bicarbonate (13 mg), methanol (2 cc.) and water (0.2 cc.) is refluxed for thirty minutes. Addition of water gives a colourless solid M.P. 210211 C. (dec.). Crystallization from acetone-hexane does not raise the melting point. acetoxy 6- chloro 3,8 hydroxypregna 4,6 dien 20- one shows in the ultra-violet maxima of absorption of 236 m 243 m (e=23,400), 252 m and 287 mp. (6:142

A mixture of 17ot-aoetoxy-G-chloro-6-dehydroprogesterone (50 mg), dry tetrahydrofuran (1 cc.), lithium aluminum t-ritertiary butoxy hydride (76.2 mg.), is stirred at room temperature for four hours. The excess of hydride is destroyed by acetone and a saturated solution of ammonium sulfate is added. The mixture is extracted with CH CI washed with saturated sodium chloride, dried and evaporated. Crystallization of the residue from acetone-hexane gives 17u-acetoxy-313- hydroxy-6-chloropregna-4,6-dien-20-one, M.P. 213 C. (dec.) identical with the pro-duct obtained above, as shown by infra-red spectroscopy.

Example 8.] 7 a-acetoxy-d -ch l0r0-6-dehydroprogesterone To a solution of 17a-acetoxy-3fi-hydroxy-6-chloropregna-4,6-dien-20-one (50 mg.) in acetone (5 cc.) at 0 C. is added dropwise with stirring a solution of 8 N chromic acid (0.15 cc.) and then the mixture is immediately poured in ice-water and extracted with methylene chloride. The organic solution is washed free of acid, dried and evaporated. The residue is 17a-acetoxy- 6-chloro-6-dehydroprogesterone. The infra-red and the ultra-violet spectra are identical with that of an authentic sample of 17a-acetoxy-6-chloro-6-dehydroprogesterone.

Alternatively, a mixture of 17a-acetoxy-6-chloro-3fihydroxypregna-4,6-dien-20-one (275 mg.) aluminum isopropoxide (300 mg), acetone (1.2 cc.) and benzene (15 cc.) is stirred for twenty-four hours at room temperature. The benzene solution is diluted with ether and the organic solution is washed with cold dilute sulfuric acid, then water. After drying and evaporation, the residue is a resin. Spectral analyses in the infra-red and ultra-violet indicate that this crude compound contains about 30% of 17u-acetoxy-6-chloro-6-dehydroprogesterone.

Example 9.-3/3,17fl-diacetoxyandrostl-en-fi-one To a solution of 3p,17 3-diacetoxy-5a-hydroxyandrostan-6-one [Leo Knot, Ann. 647, 53 (1961)] (6.6 g.) in dry pyridine (66 cc.) at 0 C., is added dropwise at such a rate as to maintain the temperature at 0 C., a solution of thionyl chloride (6.6 cc.) in dry pyridine (15 cc.).

9 The solution is stirred for one hour at C.; then it is poured in ice-water and the resulting solid is filtered and washed with water. The solid is dissolved in methylene chloride and the organic solution is washed with dilute sulfuric acid and then with water to neutrality.

After drying and evaporating the solvent a solid M.P. 165-169" C., representing crude 33,17,8-diacetoxyandrost- 4-en-6-one is obtained. Crystallization from methanol yields the pure compound M.P. 172-l74 C.,

The ultra-violet spectrum shows a maxima of absorption at 236 m with an extinction coefficient of 6930.

Calcd. for C H O C%, 71.10; H%, 8.30. Found: C%, 70.89; H%, 8.22.

Example J0.6-chl0r0-3,8,175-diacet0xyandr0sta- 4,6-dz'ene A mixture of 3 3,17,3-diacetoxyandrost-4-en-6-one (3.93 g.), phosphorus pentachloride (3.93 g.) and carbon tetrachloride (294 cc.) is stirred at room temperature for 30 minutes; then pyridine (19.6 cc.) is added and the solution is poured on ice-water. This mixture is extracted with ether and the ethereal solution is washed successively with water, sodium bicarbonate and water.

After drying the solvents and evaporating to dryness, the residue is taken in methanol and the resulting solid is filtered, yielding 6 chloro-3fi,17,8-diacetoxyandrosta- 4,6-diene M.P. 159l61 C. Further crystallization from methanol yields the pure chloro-derivative M.P. 160-161 C. [a] -73.7. The ultra-violet spectrum shows maxima of absorption at 233.5 m 243 Ill 1., and 251 m with extinction coefficients of 20400, 22900 and 15500.

Calcd. for C H O Cl: C%, 67.87; H%, 7.68; Cl%, 8.72. Found: C%, 68.01; H%, 7.68; Cl%, 8.86.

In the same manner, the 3p,17fi-diacyloxyandrost-4- en-6-ones, obtained in the same manner as described in Example 9, yield the corresponding 6-chloro-3/8,17,B- diacyloxyandrosta-4,6-dienes which are hydrolyzed to 6- chloro-Sfl,17fi-dihydroxyandrosta-4,6-diene which is oxidized in turn to 6-chloroandrosta-4,6-diene-3,17-dione.

Example I1.-3fi-acet0xy-6-chloroclzolesta- ,6-diene A mixture of 3/3-acetoxycholest-4-en-6-one [M. Heilborn, C. R. H. Jones, F. 1. Spring, J. Chem. Soc. (1937) 801] (1.79 g.), phosphorus pentachloride (1.79 g.) and carbon tetrachloride (90 cc.) is stirred at room temperature for 90 minutes. At the end of that time, pyridine (9 cc.) is added and the solution is poured in ice-water. This mixture is extracted with ether and the organic solvents are washed with sodium bicarbonate and water to neutrality.

After drying and evaporating the solvents, the gummy residue is chromatographed on alumina. The pure 3;;- acetoxy-6-chlorocholesta-4,6-diene is eluted with mixtures of benzene and hexane. The ultra-violet spectrum shows maxima of absorption at 236 m 243 Ill 1., and 251 m with extinction coefficients of 18600, 21200, and 14100.

Example 12.-6-chlore-318-hydr0xych0lesta-4,6-diene A mixture of 3B-acetoxy-6-chlorocholesta-4,6-diene (1.1 g.), potassium bicarbonate (251 mg), methanol (45 cc.) and water (4.5 cc.) is refluxed under nitrogen for 30 minutes. To the still hot solution, water is added and the resulting crystalline compound is filtered M.P. l81-185 C.

Further crystallization from methanol gives the pure 6-chloro-3fi-hydroxycholesta-4,6-diene M.P. 179-181 C. The ultra-violet spectrum shows maxima absorption at 237 m 244 m and 253 m with extinction coefficients of 18200, 21300 and 14200.

In the same manner, the 3p-acyloxycholest-4-en-6- ones, obtained as in Example 11, yield the corresponding 3fi-acyloxy-6chlorocholesta-4,6-dienes, which are hydroto lyzed to 6-chloro-3 8-hydroxycholesta-4,6-diene which is in turn oxidized to 6-chlorocholesta-4,6-dien-3-one.

A mixture of 430 mg. 3,8,l7a-diacetoxypregn-4-ene-6, 20-dione, described in the co-pending US. patent application Serial No. 285,210, mg. potassium bicarbonate, 15 cc. of methanol and 1.5 cc. of Water is refluxed under nitrogen for 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The organic layer is Washed with water to neutrality, dried and evaporated. The residue is crystallized from ether, M.P. 214.5- 222" C.

Calcd. for (3 11 0 C%, 71.11; H%, 8.30. Found: C%, 71.39; H%, 8.16.

Example 14.I 7ot-acetoxy-3f3- [3'-(cycl0pentyl) propionyloxy-p;'egn-4-ene-6,20-di0ne A mixture of 9.0 of crude l7a-acetoxy-3fi-hydroxypregn-4-ene-6,20-dione obtained as in Example 13, 90 cc. of pyridine and 9 cc. of cyclopentylpropionyl chloride is left at room temperature overnight. The mixture is poured into ice-water and extracted in ether. The ether is Washed with dilute sulfuric acid, water, sodium bicarbonate and water. After drying and evaporating the ether, the residue is a tan foam. Pure l7a-acetoxy-3fi[3'-(cyclopentyl)]-propionyloxypregn-4-ene-6,20-dione is obtained by chromatography on alumina and by crystallization from methanol, M.P. 163167 C.

Calcd. for C H G C%, 72.63; H%, 8.65. Found: C%, 72.70; H%, 8.48.

A mixture of 9.4 g. of crude l7oc-21C6tOXY-3B-hYdlOXY- pregn-4-ene-6,20-dione obtained as above, 94 cc. of pyridine and 9.4 cc. of hexanoic :anhydride is left at room temperature for 36 hours. The product is worked up as above. The residue is chromatographed on alumina and crystallized from methylene chloride-hexane, M.P. 159- 160 C.

Calcd. for (3 11 0 C%, 71.58; H%, 8.70. Found: C%, 71.45; H%, 8.82.

In the same manner, other carboxylic acid esters of 17aacetoxy-3,B-hydroxypregn-4-ene-6,20-dione are prepared by reacting the appropriate acid anhydride or acid chloride in pyridine with the starting material. In this manner there are obtained 17a-acetoxy-3B-propionyloxypregn-4-ene-6,20-dione, 17a-acetoxy-3fi-butyryloxypregn-4-ene-6,20-dione, 17ol-acetoxy-3fi-valeryloxyp-regn-4-ene-6,20-dione, 1741-21C6tOXY-3fi-llcpiElnOYlOXYpI6g11-4-6l'l6-6,20-dl0l'l6, l7a-acetoxy-3fi-octanoyloxypregn-4 ene-6,ZO-dione, 17a-acetoxy-3fi-benzoyloxypregn-4-ene-6,20dione, and 17a-acetoxy-3fi-phenylacetoxypregn-4-ene-6,20-dione.

Example J6.17a-acetoxy-6-chl0r0-3/3-hexan0yl0xypregna-4,6-zlie1z-20-0ne To a solution of 5.05 g. of l7a-acetoxy-3dhexanoyloxypregn-4-ene-6,20-dione, obtained as in Example 15, 5.05 g. of phosphorus pentachloride is added. After stirring for 30 minutes at room temperature, 10 cc, of pyridine are added. The product is worked up as described above. The residue is chromatographed on alumina to yield, after crystallization-from methanol l7oc-acetoxy-6 chloro-3fl-hexanoyloxypregnat,6-dien-2O-0ne.

Calcd. for C H., C Cl: C%, 68.95; H%, 8.32; Cl%, 7.03. Found: C%, 68.95; H%, 8.18; Cl%, 7.00, 6.93.

A mixture of 6.1 g. of PCl and a solution of 6.1 g. of 17 acetoxy 3B-[3'-(cyclopentyl)]-propionyloxypregn-4 ene-6,20-dione, obtained as in Example 14, in 300 cc. of CCL; is stirred for 30 minutes at room temperature. The

reaction mixture is worked up as described above. The residue is a foam which is chromatographed on alumina. Fractions eluted with mixtures of benzene-hexane and pure benzene are combined and crystallized from methanol to yield 17:! acetoXy-6-chloro-3fi-[3'-(cyclopentyl)]-propionyloXypregna-4,6-dien-20-one, M.P. 109-112" C.

Calcd. for C H O CI: C%, 70.10; H%, 8.11; (11%, 6.68. Found: C%, 69.85; H%, 8.21; 01%, 6,69, 6.57.

In the same manner by reacting 17a-acetoxy-3fi-acyloxypregnt-ene-6,20-diones with PCl under conditions as above, 170: acetoXy-3 8-acyloXy-6-chloropregna-4,6-dien- 20-ones, are obtained, in which the acyloXy group is propionyloxy, buturyloxy, valeryloxy, heptanoyloxy, octanoyloxy, benzoyloxy and phenylacetoxy, respectively. Other 17-carboxylic acid esters of 3 fl-acetoxy-l7ot-hydroxypregn- 4-ene-6,20-diones such as the 17a-propionate, butyrate, valerate and hexanoate and other 3,8,17a-diacyloxypregn- 4-ene-6,20-diones such as the 313,170t-diPl'OPl-OHY1OXY, 3B, 17a-dibutyry1oxy, 3p,17et-divaleryloxy, and 3fi,l7a-dihexanoyloXypregn-4-ene-6,20-diones are transformed by PCl to the corresponding 3p-acetoxy-17a-acyloxy-6-chloropregna 4,6 dien-ZO-ones and 6-chloro-3B,17-diacyloxypregna-4,6-dien-20-ones. The appropriate 3,B,17u-diacyloxy compound for these transformations are obtained by hydrolysis of the corresponding 3;8-acetoxy-17a-acyloxy compounds and re-esterification with the appropriate acylating agents as described above.

Hydrolysis of the above compounds in the manner described in Example 3 yields the corresponding 17a-acy1- oxy 6-chloro-3fl-hydroxypregna-4,6-dien-20-ones, which are in turn oxidized to the corresponding 17ot-acyloxy-6- chloro-6-dehydroprogesterones.

Example I 8.3;3-acet0xy-6-chl0ro-andrasta-4,6-dien- 1 7 -one A mixture of 600 mg. of 3fi-acetoxyandrost-4-ene-6,17- dione, prepared by dehydration with thionyl chloride in pyridine of the known 3B-acetoxy-Sa-hydroxyandrostane- 6,20-dione (L. Knof, Ann. 1962, 657, 174) as described in the co-pending US. patent application Serial No. 285,210, 600 mg. PO1 and 35 ml. of carbon tetrachloride is stirred for 30 minutes at room temperature. After the usual work-up, the residue is purified by chromatography or alumina to yield 3fl-acetoxy-6-chloro-androsta-4,6-diene- 17-one, M.P. 194-1955 I claim:

1. A process for preparing steroidal 6-chloro-4,6-dienes selected from the group consisting of pregnanes, androstanes and cholestanes, characterized by possessing the following structure in rings A and B in which Y is selected from the group consisting of acyloxy, hydroxy and ketonic oxygen groups, comprising bringing into contact with each other a steroidal 3,3-acyloxy-A -6-ketosteriod selected from the group consisting of pregnancs, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B Acyl 0 hydrolyzing said last-named compound in a basic medium to yield the corresponding steroidal 6-chloro-3p-hydroxy- 4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, characterized by possessing the following structure in rings A and B and oxidizing said last-named compound to obtain the corresponding steroidal 6-chloro-3-keto-4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B 2. A process as defined in claim 1, in which Y represents an acyloxy group, comprising bringing into contact with each other a steroidal 3fi-acyloxy-A -6-ketosteroid selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B and phosphorus pentachloride in an inert, non-reactive solvent selected from the group consisting of carbon tetrachloride, ethyl acetate, and aromatic hydrocarbons with a boiling point below C., to yield a steroidal 3 p-acyloxy-6-chloro-4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and possessing the following structure in rings A and B 3. A process as defined in claim 1, in which Y represents the hydroxyl group, comprising bringing into contact with each other a steroidal 3[3-acyloxy-A -6-ketosteroid selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B l Acyl O@ i) and phosphorus pentachloride in an inert, non-reactive solvent selected from the group consisting of carbon tetrachloride, ethyl acetate, and aromatic hydrocarbons with a boiling point below 150 C., to yield a steroidal 3fl-acyloxy-6-chloro-4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and possessing the following structure in rings A and B l Acyl o l and hydrolyzing said last-named compound in a basic medium to yield the corresponding steroidal 6-chloro- 3,8-hydrXy-4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A andB 4. A process as defined in claim 1, in which Y represents the ketonic oxygen group, comprising bringing into contact with each other a steroidal 3fi-acyloXy-A -6- ketosteroid selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B and hydrolyzing said last-named compound in a basic medium to yield the corresponding steroidal 6-chloro- 3,8-hydroXy-4,6-diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B and oxidizing said last-named compound to obtain the corresponding steroidal 6-chloro-3-keto-4,6 diene selected from the group consisting of pregnanes, androstanes, and cholestanes, and characterized by possessing the following structure in rings A and B 5. A process for the production of pregnane derivatives having the following structural Formula (i) in which Y represents a substituent selected from the group consisting of acyloxy, hydroxy, and ketonic oxygen groups, in which R is a substituent selected from the group consisting of hydrogen, acyloxy, and straight-chain lower alkyl groups containing from 1 to 4 carbon atoms, and X represents a substituent selected from the group consisting of hydrogen and fluorine, comprising bringing into contact with each other a Sfi-acyloxy-G-ketopregn- 4-ene of the following structural Formula (ii) 0 HaX (1:0 iii Acyl 0 an in which R and X have the significance defined above, 15

and phosphorus pentachloride in an inert, non-reactive solvent selected from the group consisting of carbon tetrachloride, ethyl acetate and aromatic hydrocarbons with a boiling point below 150 C., to obtain a 313- acyloxy-6-chloro-4,6-pregnadiene of Formula (i) in which Y represents an acyloxy group, and R and X have the significance defined above, hydrolyzing said last named compound in a basic medium, to obtain the corresponding compound of Formula (i) in which Y represents the hydroxyl group, and R and X have the significance defined above, and oxidizing said last-named compound to obtain the corresponding 6-chloro-6-dehydroprogesterone of the general structure (i) in which Y represents the ketonic oxygen group, and R and X have the significance defined above.

References Cited by the Examiner Djerassi-Steroid Reactions, pp. 138 and 146 (1963 Holden-Day, Inc., San Francisco, California.

LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner. 

5. A PROCESS FOR THE PRODUCTION OF PREGNANE DERIVATIVES HAVING THE FOLLOWING STRUCTURAL FORMULA (I) 